The sequestered native Hawaiian population with a high incidence and poor survival of cancer, particularly of the lung and breast, will provide a unique population for family studies of the natural killer cell (NK) system. Virtually no reports on cancer family studies and NK function have been published. This immunobiology research will be directed towards the role of the NK system and effector cell function as a natural immunosurveillance mechanism in tumorgenesis. NK cells, known for their cytotoxic effects against tumor cells, may have important immunoregulatory functions and the potential for positive self regulation as shown by their ability to produce interferon and other cytokines. This proposed research will test the hypothesis that in immunodeficiency in NK function is associated with increased incidence of cancer and poorer survival of the native Hawaiian population. Thus, NK function will be compared in the Hawaiian case and control families. In addition, this family study will provide an ideal opportunity to study its immunogenetic basis in association with HLA determinants. In preliminary studies, selected Hawaiian case families will be HLA typed to indicate whether there is a direct segregation of NK function with HLA haplotype. In a prospective analysis of Hawaiian cancer patients, NK cells and effector cell function will be correlated with the effect of chemotherapy, irradiation and/or immunotherapy to identify immune functions which may be deficient and related to their poorer survival. Thus, the assessment of multiple immunologic parameters may provide a basic understanding of immunoregulatory cellular interactions involved in NK function. The ultimate goal in this study of the NK system will be the elucidation of immunologic and genetic factors which may provide valuable insights into the pathogenesis of cancer. The NK system may prove useful in understanding tumor biology and ultimately, in cancer therapy through immunologic reconstitution in the immunosuppressed host.